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Insulin is secreted by the β‐cell in response to various stimuli. However, peripheral insulin concentrations may be an imperfect measure of insulin secretion because they represent the net sum of two opposing processes. The first is actual insulin secretion into the portal vein while the second is hepatic extraction of insulin that occurs across the liver as insulin reaches the systemic circulation. It is uncertain whether hepatic extraction is an active or a passive process, but it is likely proportional to the magnitude of insulin secretion [32] and declines as β‐cell function declines [33].

C‐peptide arises from the post‐translational processing of insulin as preproinsulin which folds upon itself to form specific disulfide bonds, resulting in a dimeric structure after cleavage of the connecting (C‐)peptide. This peptide is secreted in a 1:1 ratio with insulin but does not undergo hepatic extraction. Therefore, in theory, C‐peptide concentrations serve as a better measure of insulin secretion than do insulin concentrations themselves. However, C‐peptide which is cleared by the kidney (and therefore cannot be used reliably in renal dysfunction or failure) has a half‐life of ~30 minutes and therefore accumulates in the circulation compared to insulin (half‐life of < 5minutes). Deconvolution of insulin secretion rates from C‐peptide concentrations requires knowledge of the kinetics underling C‐peptide clearance. This can be estimated from anthropometric criteria thanks to the work of Van Cauter et al. so that insulin secretion can be measured accurately in humans with intact renal function [34, 35].

The other factor when assessing insulin secretion is the nature of the stimulus – a physiological stimulus mimicking situations similar to everyday life e.g. an oral glucose tolerance test or a mixed meal tolerance test may be better at detecting subtle defects in insulin secretion as compared to supraphysiologic stimuli. The latter use stimuli intended to produce submaximal insulin secretion e.g. glucagon or arginine stimulation tests [36–38]. Similarly, an intravenous bolus of glucose that can change peripheral concentrations of glucose very rapidly (as part of an intravenous glucose tolerance test – IVGTT) is also a supraphysiologic stimulus to β‐cell secretion. Intravenous glucose challenges produce a characteristic biphasic pattern of insulin secretion in healthy subjects that is not observed in people with early type 1 diabetes or in people with type 2 diabetes [39].

While isolated measurement of insulin secretion in response to a standardized stimulus might provide a qualitative measurement of β‐cell function, truly quantitative measures require expressing insulin secretion as a function of insulin action. Such indices generated through mathematical modelling can predict risk of progression to diabetes or quantify response to an intervention. However, at present they have limited utility on an individual basis due to lack of sufficient normative data [6]. Nevertheless, absent or near absent C‐peptide concentrations in the fasting state or in response to stimuli may help demonstrate an absence of endogenous insulin secretion.